HCV is a single stranded, positive-sense RNA virus belonging to the Flaviviridae family of viruses in the hepacivirus genus. The viral genome translates into a single open reading frame that encodes for multiple structural and non structural proteins.
The NS5A protein of HCV is located downstream of the NS4B protein and upstream of the NS5B protein. Upon posttranslational cleavage by the viral serine protease NS3/4A, the NS5A matures into a zinc containing, three-domain phosphoprotein that either exists as a hypophosphorylated (56-kDa, p56) or hyperphosphorylated species (58-kDa, p58). NS5A of HCV is implicated in multiple aspects of the viral lifecycle including viral replication and infectious particle assembly as well as modulation of the environment of its host cell. Although no enzymatic function has been ascribed to the protein it is reported to interact with numerous viral and cellular factors.
A number of patents and patent applications disclose compounds with HCV inhibitory activity, in particular targeting NS5A. WO2006/133326 discloses stilbene derivatives while WO 2008/021927, WO 2008/021928, WO2009102325 and WO2009/102318 disclose biphenyl derivatives having NS5A HCV inhibitory activity. US2009/0202483 discloses bridged biphenyl derivatives. WO 2008/048589 discloses 4-(phenylethynyl)-1H-pyrazole derivatives and their antiviral use. WO 2008/070447 discloses a broad range of HCV inhibiting compounds including a benzimidazole moiety. WO2010/099527. WO2010/065668, WO2010/065674 and WO2010/065681 disclose benzimidazole-imidazole derivatives as HCV NS5A inhibitors. For instance, compounds having the following structure and Chemical Abstracts Number are disclosed in Table 1 of WO2010/065674:
TABLE AChemical Abstracts Number (CAS),CAS name and compound referenceStructure of WO2010/065674number in WO 2010/065674CAS 1242087-93-9-Compound 174 N-[(1S)-1-[[(2S)-2-[5-[6-[2-[(2S)-1-[(2S)-2-[(methoxy- carbonyl)amino]-3-methyl-1-oxobutyl]-2- pyrrolidinyl]-1H-benzimidazol-6-yl]-2-naphthalenyl]- 1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2- methylpropyl]-carbamic acid, methyl ester CAS 1242087-95-1-compound 176 N-[(1S,2R)-2-methoxy-1-[[(2S)-2-[5-[6-[2-[(2S)-1- [(2S,3R)-3-methoxy-2-[(methoxy-carbonyl)amino]- 1-oxobutyl]-2-pyrrolidinyl]-1H-benzimidazol-6-yl]-2- naphthalenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl] carbonyl]propyl]-carbamic acid, methyl ester CAS 1228552-40-6-compound 177 N-[(1S)-1-[[(2S)-2-[5-[6-[2-[(2S)-1-[(2R)-2-(dimethyl- amino)-2-phenylacetyl]-2-pyrrolidinyl]-1H- benzimidazol-6-yl]-2-naphthalenyl]-1H-imidazol- 2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]- carbamic acid, methyl ester Compound 179 Compound 181 CAS 1228552-49-5-compound 182 N-[(1S)-1-[[(2S)-2-[6-[6-[2-[(2S)-1-[(2R)-2- (dimethylamino)-2-phenylacetyl]-2-pyrrolidinyl]-1H- imidazol-5-yl]-2-naphthalenyl]-1H-benzimidazol-2- yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]- carbamic acid, methyl ester
Following the initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. Chronic hepatitis can progress to liver fibrosis, leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations.
There are six major HCV genotypes and more than 50 subtypes, which are differently distributed geographically. HCV genotype 1 is the predominant genotype in Europe and in the US. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to current therapy.
Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades.
Current HCV therapies are based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy yields a sustained virologic response in 40% of patients infected by genotype 1 HCV and about 80% of those infected by genotypes 2 and 3. Beside the limited efficacy on HCV genotype 1, this combination therapy has significant side effects including influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Hence, in order to overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, the emerging of resistance, and compliance failures, as well as to improve the sustained viral load response, there is a need for more effective, convenient and better-tolerated treatments.
The present invention concerns a group of benzimidazole-imidazole derivatives capable of inhibiting the HCV replication cycle.
Compounds of the present invention are also attractive due to the fact that they show a greater selectivity to inhibit the HCV replication cycle when compared to their capacity to inhibit the HIV replication. HIV infected patients often suffer from co-infections such as HCV. Treatment of such patients with an HCV inhibitor that also inhibits HIV may lead to the undesired emergence of resistant HIV strains.